Inhalation device having an optimized air flow path

ABSTRACT

A device for the pulmonary delivery of a compound comprising a reservoir for storing a compound, a system for generating particles of a desired size, and a housing comprising an inlet and an outlet between which is formed a substantially unobstructed airflow path.

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/271,193 filed Feb. 23, 2001.

FIELD OF THE INVENTION

[0002] The present invention generally relates to a device for thepulmonary delivery of an aerosolized compound. The device isparticularly suitable for the pulmonary delivery of a pharmaceuticalcompound but may be used for other purposes.

BACKGROUND OF THE INVENTION

[0003] The following description of the background of the invention isprovided to aid in understanding the invention, but is not admitted tobe or to describe prior art to the invention.

[0004] Recently there has been interest in developing devices andmethods to systemically deliver pharmaceutical compositions,particularly those comprising a protein or peptide as the prophylacticor therapeutic agent, via or through the lungs of the patient. There arecurrently three primary device types for the delivery of pharmaceuticalsto the respiratory tract.

[0005] One such device type is the metered dose inhaler (“MDI”). MDIsuse pressurized gas or propellant to deliver a burst of the compound orpharmaceutical into the patient's mouth during inhalation. A second typeis the dry powder inhaler (“DPI”). DPIs use a burst of air to draw adose of inactive powder into the bronchial tract. A third device type isa nebulizer. Nebulizers deliver the pharmaceutical through generating anaerosol by atomizing a liquid.

[0006] These conventional device types, however, are not desirable fordelivery of certain pharmaceuticals, particularly those intended forsystemic administration to the patient. There are many reasons why theseconventional devices are not desirable. For example, the precision ofdose control and delivery of conventional devices such as MDIs, DPIs,and nebulizers is less accurate for pulmonary delivery, which is ofparticular concern where specific dosages or dosing regimens arerequired. Another reason is that pharmaceutical compositions oftenbecome attached to or stuck on the side of the device during delivery,thus decreasing the dosage. These devices are also dependent on usertechnique, which makes dosages variable from person to person and doseto dose.

[0007] Thus there is a need to provide devices that are capable ofefficient, effective, and consistent delivery of desired dosages of asystemic pharmaceutical to a patient via the pulmonary route.

SUMMARY OF THE INVENTION

[0008] An embodiment of this invention provides devices for delivery ofan aerosolized compound, such as a pharmaceutical compound, to a patientvia the pulmonary route, using an electronic ejection device. Anembodiment of this invention comprises air paths specifically designedto minimize turbulence.

[0009] Advantageously, an embodiment of the present invention providesless deposition of aerosolized compound within the inhaler and a moreeffective transfer of the dispensed material into the inhaled airstream.

[0010] One embodiment of the present invention relates to a device thatcomprises a reservoir for storing a compound, wherein a reservoir isfluidly connected to a system for generating liquid particles of adesired size (or size range) containing a compound. This systemcomprises an entry port and an element to generate particles of thedesired size for ejection from an ejection head of the element. At leastthe ejection head of the particle-generating element is disposed withina housing designed to generate a substantially unobstructed airflowpath, substantially non-turbulent airflow, or substantially laminarairflow for delivery of the compound. The housing comprises an inlet andan outlet, and provides for substantially unobstructed airflow betweenthe ejection head and the outlet when air traverses the airflow pathfrom inlet to outlet. In one embodiment, the ejection head is disposedin the airflow path downstream of the inlet and upstream from theoutlet.

[0011] Another embodiment of the invention relates to a method fordelivering an aerosolized compound to a patient using a device accordingto the invention. Such a method comprises inhaling air through such adevice while the particle-generating system of the device is actuated.Use of the term “while” encompasses during, immediately thereafter,immediately before, or any such moment that is temporally closelyrelated.

[0012] Another embodiment of the invention relates to a method forgenerating an air stream containing a compound. This method comprisesdrawing air through a device of the invention from inlet to outlet whileactuating the particle-generating system of the device.

[0013] Further features and advantages of the invention as well as thestructure and operation of various embodiments of the invention aredescribed in detail herein with reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The present invention will be described with particularembodiments thereof, and references will be made to the drawings inwhich:

[0015]FIG. 1 illustrates one embodiment of the device according to theinvention; and

[0016]FIG. 2 illustrates a system to generate particles of the desiredsize according to an embodiment of the invention.

[0017] These drawings are included for illustrative purposes and are inno way intended to limit the scope of use or design of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0018] The reservoir and particle-generating system of a deviceaccording to the invention may be disposed within, partially within, oroutside of the housing of the device. The reservoir, if included, withinthe housing, may be aerodynamically shaped. In another embodiment, thereservoir is detachable and/or replaceable. In another embodiment, thereservoir and particle-generating system are integrated into a singledetachable and/or replaceable unit.

[0019] The system for generating particles can be any system thatgenerates particles of the desired size or size range. In oneembodiment, this system is a digitally controlled electronic dropletejection device. Other embodiments of digitally controlled electronicdroplet ejection devices useful in the practice of the invention includethose that use heat or a piezoelectric component to generate particlesthat are ejected from the ejection head.

[0020] The size of the particles is a size that allows the particles totransit to and be deposited in the alveoli. This size may be where atleast about 90% of the particles range in size from about 1 μm to about5 μm such as where the particles have a mass median aerodynamic diameterof about 3 μm. For example, at least about 60% of the particles may havea mass median aerodynamic diameter of about 3 μtm.

[0021] The housing may be of any size, shape and matter that allows forsubstantially unobstructed airflow. The airflow may be substantiallylaminar prior to exiting the housing outlet. The housing's inner surfaceproximal to the ejection head and extending to the outlet may becontoured to minimize turbulence. This substantially unobstructedairflow may comprise a substantially homogeneous mixture of the ejectedcompound and air in the airflow prior to exiting the housing outlet.

[0022] The term “reservoir” shall be interpreted to mean any containerwhich is suitable to hold and store a compound. The reservoir may be ofany shape, size, or material and may be aerodynamically designed so asto facilitate airflow and decrease obstructions in the airflow path. Therelative size and optimal shape of the reservoir with respect to othercomponents is variable. For example, altering the size and/or shape ofthe reservoir may have an impact on the aerodynamics of the system. Thereservoir may have an outer layer of material which may beaerodynamically designed, and an inner collapsible bag which is suitableto hold and store a compound. The reservoir is filled with a compound tobe administered and may be sealed or have a vent hole through the outermaterial to allow air displacement for the inner collapsible bag. Thereservoir is fluidly connected to the system and may be eitherpermanently connected or may be detachably connected so as to refill thereservoir with a compound.

[0023] The term “system” or “particle-generating system” shall beinterpreted to mean any device that can act as an ejection means toeject particles into the airflow. By way of nonexclusive example, thesystem may compromise a piezoelectric device, such as the kinds (thermaland piezo) used in ink jet printing.

[0024] The term “particles” shall be interpreted to mean small dropletsof the compound which are formed upon ejection from the ejection head ofthe element.

[0025] The term “desired size” shall be interpreted to mean a size whichis sufficiently small such that when the particles are formed, theyremain suspended in the air for a sufficient amount of time such thatthey may be inhaled and are sufficiently small such that the particlesmay be deposited in alveoli upon reaching the lungs. The particles mayrange in size from about 1 μm to about 5 μm in diameter, such as a massmedian aerodynamic diameter of about 3 μm.

[0026] A compound stored in the reservoir of the system can be in anyform, and is preferably a liquid formulation. The compound may be anypharmaceutical compound, for example, a protein, a small molecule, or agene delivery vehicle. Preferred protein embodiments include EPO, G-CSF,GM-CSF, insulin, hGH, factor VIII, FSH, LH, VEGF, an interferon, aninterleukin, an antibody or antibody fragment (alone or conjugated toanother compound, for example, a cytotoxic agent). Small moleculeembodiments include nicotine, methotrexate, albuterol, methadone, orcromylin. Still other embodiments of pharmaceutical compounds include agene delivery vehicle such as a virus, a liposome, a nucleic acid, anucleic acid complex, or suspensions thereof.

[0027] The term “compound” shall be interpreted to mean any fluid orliquid formulation such as any pharmaceutical compound.

[0028] The term “small molecule” shall be interpreted to mean anymolecule having fewer than one hundred (100) non hydrogen atoms, andhaving a molecular weight of less than about 1 kDalton.

[0029] The term “fluidly connected” shall be interpreted to mean aconnection whereby a fluid may be transferred from the reservoir to thesystem. This fluid connection may be accomplished in any known way.Non-exclusive examples of such a connection are gravity, a pump, achannel, or capillary feed.

[0030] The term “entry port” shall be interpreted to mean the area orpoint at which the compound enters the system.

[0031] The term “element to generate particles” shall be interpreted tomean any delivery engine which can generate particles of the desiredsize.

[0032] The term “ejection head” shall be interpreted to mean the area orpoint on the system where the particles of the compound are ejected intothe air stream.

[0033] The term “housing” shall be interpreted to mean any casing orencased area in which air may flow.

[0034] The term “inlet” shall be interpreted to mean the area or pointat which air enters the housing.

[0035] The term “outlet” shall be interpreted to mean the area or pointat which air exits the housing.

[0036] The term “airflow path” shall be interpreted to mean the paththat the air follows from the inlet to the outlet of the housing.

[0037] The term “disposed” shall be interpreted to mean that theejection head is connected in any way to the housing such that theejection head is downstream of the inlet and upstream of the outlet.This connection may be aerodynamically designed such as to decreaseairflow obstructions and decrease turbulence in the airflow path.

[0038] The term “substantially unobstructed airflow” shall beinterpreted to mean where the airflow path is substantially free ofobstructions such as to decrease turbulence. By way of non-exclusiveexample, this may be accomplished by way of an aerodynamic airflow path.

[0039] The term “pharmaceutical compound” shall be interpreted to meanany molecule or combination of molecules which are capable of performinga pharmaceutical function, e.g., a drug or prodrug which is effective inhelping to prevent or treat a disease or condition. “Effective inhelping to prevent or treat a disease or condition” indicates thatadministration in a clinically appropriate manner results in abeneficial effect for at least a statistically significant fraction ofpatients, such as a improvement of symptoms, a cure, a reduction indisease load, reduction in tumor mass or cell numbers, extension oflife, improvement in quality of life, or other effect generallyrecognized as positive by medical doctors familiar with treating theparticular type of disease or condition. The term “pharmaceuticalcompound” includes but is not limited to any protein, small molecule orgene delivery system.

[0040] Prodrugs include chemical derivatives of a biologically-activeparent compound which, upon administration, will eventually liberate theactive parent compound in vivo. Use of prodrugs allows the artisan tomodify the onset and/or duration of action in vivo. In addition, the useof prodrugs can modify the transportation into, the distribution orsolubility of a drug in the body. Furthermore, prodrugs may reduce thetoxicity and/or otherwise overcome difficulties encountered whenadministering a parent pharmaceutical compound.

[0041] Pharmaceutical compositions of the present invention may bemanufactured in a manner that is itself known, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilizing processes.

[0042] Pharmaceutically acceptable compositions for use in accordancewith the present invention thus may be formulated in conventional waysusing one or more physiologically acceptable carriers comprisingexcipients which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Examples include butare not limited to surface tension-controlling agents, humectants, andviscosity-controlling agents; proper formulation may be dependent uponthe specific pharmaceutical compound.

[0043] The term “gene delivery vehicle” shall be interpreted to mean anymethod of delivering an intact gene into an organism such as adenoviralparticles or other viruses modified for gene delivery, naked DNA,degradable matrices, and/or such gene delivery systems as mentioned inDan Luo and W. Mark Saltzman, Synthetic DNA Delivery Systems, NatureBiotechnology, January 2000, at 33-37, which is incorporated herein byreference in its entirety.

[0044] The term “electronic ejection device” shall be interpreted tomean any device which uses electronics to produce and eject particles ofthe desired size. The electronic ejection device includes, but is notlimited to, a thermal device or a piezoelectric device such as thosedescribed in U.S. Pat. No. 5,894,841, which is incorporated herein byreference in its entirety.

[0045] The term “uses heat to generate particles” shall be interpretedto mean a thermal device which produces particles of the desired sizeusing heat, such as described in U.S. Pat. No. 5,894,841. A typicalthermal device comprises a liquid containing chamber provided with aconfigured array of nozzles and thin film resistors. A resistor istypically located directly behind each nozzle, for a given nozzleconfiguration. Each nozzle supplies a droplet or droplets (sometimessatellite droplets are created) of liquid from the chamber if and when ashort electrical pulse energizes the corresponding resistor. Theresistors thus function as an electronic ejection device. Within a fewmicroseconds liquid in contact with the resistor is vaporized and formsa bubble. The vapor bubble grows rapidly and imparts momentum to liquidadjacent to a bubble. Some of this liquid is ejected as a droplet froman adjacent nozzle. The ejected volume of liquid is then automaticallyreplaced in the chamber from the reservoir by a fluid connection.

[0046] The term “piezoelectric component” shall be interpreted to mean adevice generating particles of the desired size by a pressure wave inthe fluid produced by applying a voltage pulse to a piezoelectricceramic which acts as an electronic ejection device. The fluid isejected through a fine aperture. By way of non-exclusive example, apiezoelectric device is commonly used in inkjet printing.

[0047] The term “alveoli” shall be interpreted to mean components in thepulmonary region of the lung where gas exchange occurs between the airand the lungs and the circulatory system.

[0048] The term “substantially laminar” shall be interpreted to mean asubstantially streamline steady flow at a substantially constantvelocity. Air and entrained droplet flow is said to be laminar if thesubstance moves smoothly in layers, one layer (lamina) sliding relativeto another. Viscosity and turbulence effects come into play if layers ofthe flowing substance change their shape as they move, as caused, forexample, by airflow path surface irregularities, discontinuities, or thelike.

[0049] The term “substantially homogeneous mixture” shall be interpretedto mean a mixture approaching uniform composition throughout.

[0050] The term “contoured to minimize turbulence” shall be interpretedto mean that the housing is designed such that turbulence is minimizedand that airflow is approaching substantially constant or smooth laminarflow. By way of non-exclusive example, the inner walls of the housingmay be sloped and/or smooth, or may be aerodynamically designed.

[0051] The term “aerosolized compound” shall be interpreted to mean avolume of air of which has suspended droplets comprising the compoundwithin it. For example, the volume could be greater than 2 ml and lessthan 5 liters.

[0052] The term “substantially non-turbulent airflow” shall beinterpreted to mean that the housing is designed so as to reduce and/orminimize turbulence.

[0053] One embodiment of the device is presented in FIGS. 1-2. Thedevice in FIG. 1 comprises a reservoir 1 for storing the compound to bedelivered to the patient, a system 2 to generate particles of a desiredsize and a housing 7. The system FIG. 2 comprises an entry port 4 and anelement 5 to general particles of the desired size for ejection from anejection head 6 of the element. The housing comprises an inlet 8 and anoutlet 9.

[0054] The reservoir 1 in this embodiment is disposed within and extendsalong the length of the housing 7 and is fluidly connected to the system2 at the entry port 4 and is connected to the housing at the inlet 8 byconnection to a power source 10 such as a battery. The reservoir 1pictured is a collapsible bladder, however, other forms of a reservoirmay be used. For example, the reservoir could be a cylinder fitted witha piston. The reservoir 1, in one embodiment, is sealed. The reservoir 1may also be disposable and/or replaceable.

[0055] In one embodiment, system 2 is disposed entirely or partiallywithin and extends along the length of the housing 7 and is disposed inthe airflow path downstream of the inlet 8 and upstream from the outlet9. The system 2 may also be connected to the housing by suspension-likeattachments 11 so as to keep the airflow substantially unobstructed. Theejection head 6 of the system 2 is disposed in the airflow path upstreamof the outlet so as to provide for a mixture area in which the compound,after ejection from the ejection head, mixes with the air flowing fromthe inlet 8 to the outlet 9 for delivery to the patient. In thisembodiment, the element 5 to generate particles is of the kind used in athermal ink jet printer. However, any device that will generateparticles of the desired size may be used, such as those described inU.S. Pat. No. 5, 894,841. The compound flows from the reservoir 1 intothe element 5 through the entry port 4 and particles of the desired sizeare ejected from the ejection head 6 into the airflow path “A” whichthen delivers the compound to the patient. Moreover, element 5 maycomprise a silicon wafer, and may be as thick or thin as needed.

[0056] For the pulmonary administration of pharmaceuticals, a smallparticle size is preferred. For example, particles ranging in size fromabout 1 μm to about 5 μm diameter are acceptable for the pulmonarydelivery. Particles with a mass median aerodynamic diameter of about 3μm are preferable. If necessary, the particle size can be reduced by anoptional heating element which can be employed to vaporize the liquid.Particle size can further be reduced by directing the particles ejectedfrom the ejection head 6 at each another or at a suitable target tofurther fragment the particles.

[0057] Housing 7 may provide for a substantially unobstructed airflowpath so as to minimize turbulence so that the compound stored in thereservoir 1 may be efficiently delivered to the patient. Obstructions inthe airflow path result in turbulence which results in some of thecompound not reaching the patient. When there is turbulence, particlesof the compound deposit on the side of the housing. Therefore, thephysical shape and material of the components of the device may bealtered so as to decrease turbulence. For example, the reservoir, systemand housing may be aerodynamically designed. The reservoir, system andhousing may be constructed of materials that decrease turbulence.Suspension-like attachments 11 may be employed to secure the system tothe housing to minimize obstructions and turbulence. Other forms ofattachment may be used that minimize obstructions and turbulence.

[0058] The contents of the articles, patents, and patent applications,and all other documents and electronically available informationmentioned or cited herein, are hereby incorporated by reference in theirentirety to the same extent as if each individual publication wasspecifically and individually indicated to be incorporated by reference.Applicants reserve the right to physically incorporate into thisapplication and all materials and information from any such articles,patents, patent applications, or other documents. The inventionsillustratively described herein can suitably be practiced in the absenceof any element or elements, limitation or limitations, not specificallydisclosed herein. Thus, for example, the terms “comprising,”“including”, “containing”, etc. shall be read expansively and withoutlimitation. Additionally, the terms and expressions employed herein havebeen used as terms of description and not of limitation, and there is nointention in the use of such terms and expressions of excluding anyequivalents of the future shown and described or portion thereof, but itis recognized that various modifications are possible within the scopeof the invention claimed. Thus, it should be understood that althoughthe present invention has been specifically disclosed by preferredembodiments and optional features, modification and variation of theinventions embodied therein herein disclosed can be resorted to by thoseskilled in the art, and that such modifications and variations areconsidered to be within the scope of the inventions disclosed herein.The inventions have been described broadly and generically herein. Eachof the narrower species and subgeneric groupings falling within thegeneric disclosure also form part of these inventions. This includes thegeneric description of each invention with a proviso or negativelimitation removing any subject matter from the genus, regardless ofwhether or not the excised materials specifically resided herein. Otherembodiments are within the following claims. In addition, where featuresor aspects of an invention are described in terms of the Markush group,those schooled in the art will recognize that the invention is alsothereby described in terms of any individual member or subgroup ofmembers of the Markush group.

[0059] From the description of the invention herein, it is manifest thatvarious equivalents can be used to implement the concepts of the presentinvention without departing from its scope. Moreover, while theinvention has been described with specific reference to certainembodiments, a person of ordinary skills in the art would recognize thatchanges can be made in form and detail without departing from the spiritand the scope of the invention. The described embodiments are to beconsidered in all respects as illustrative and not restrictive. Itshould also be understood that the invention is not limited to theparticular embodiments described herein, but is capable of manyequivalents, rearrangements, modifications, and substitutions withoutdeparting from the scope of the invention.

What is claimed is:
 1. A device for delivering an aerosolized compound,the device comprising: a reservoir that stores the compound; a systemcomprising an entry port and an element to generate particles of adesired size for ejection from an ejection head of the element, whereinsaid particles comprise a compound, and wherein said system is fluidlyconnected to a reservoir; and a housing comprising an inlet and anoutlet between which is formed an airflow path and in which at least theejection head is disposed in the air flow path downstream of the inletand upstream from the outlet, wherein the housing provides for asubstantially unobstructed airflow between the ejection head and theoutlet when air traverses the airflow path from the inlet to the outlet.2. A device according to claim 1 wherein the compound is stored in thereservoir in a liquid formulation.
 3. A device according to claim 1wherein the compound is a pharmaceutical compound.
 4. A device accordingto claim 3 wherein the pharmaceutical compound is selected from thegroup consisting of a protein, a small molecule, and a gene deliveryvehicle.
 5. A device according to claim 3 wherein the pharmaceuticalcompound is a protein selected from the group consisting of a hormone, areceptor, an antibody, and an enzyme.
 6. A device according to claim 3wherein the pharmaceutical compound is a small molecule drug or prodrug.7. A device according to claim 3 wherein the pharmaceutical compound isa gene delivery vehicle.
 8. A device according to claim 1 wherein thereservoir and particle-generating system are disposed within thehousing.
 9. A device according to claim 8 wherein the reservoir isaerodynamically shaped.
 10. A device according to claim 1 wherein thereservoir is detachable.
 11. A device according to claim 1 wherein thereservoir and particle-generating system are integrated into a singledetachable unit.
 12. A device according to claim 1 wherein theparticle-generating system is an electronic ejection device.
 13. Adevice according to claim 12 wherein the electronic ejection device usesheat to generate particles ejected from the ejection head.
 14. A deviceaccording to claim 12 wherein the electronic ejection device uses apiezoelectric component to generate particles ejected from the ejectionhead.
 15. A device according to claim 1 wherein the desired size of theparticles is a size that allows the particles to transit to and bedeposited in alveoli.
 16. A device according to claim 15 wherein atleast about 90% of the particles range in size from about 1 μm to about5 μm.
 17. A device according to claim 16 wherein at least about 60% ofthe particles have a mass median aerodynamic diameter of about 3 μm. 18.A device according to claim 1 wherein the substantially unobstructedairflow is substantially laminar prior to exiting the housing outlet.19. A device according to claim 1 wherein the substantially unobstructedairflow comprises a substantially homogeneous mixture of the ejectedcompound and air in the airflow prior to exiting the housing outlet. 20.A device according to claim 1 wherein the inner surface of the housingis proximal to the ejection head and extending to the outlet iscontoured to minimize turbulence.
 21. A method of delivering anaerosolized compound to a patient, the method comprising inhaling airwhich contains a compound through a device while the particle-generatingsystem of the device is actuated, wherein said device comprises: areservoir that stores the compound; a system comprising an entry portand an element to generate particles of a desired size for ejection froman ejection head of the element, wherein said particles comprise thecompound, wherein said system is fluidly connected to a reservoir; and ahousing comprising an inlet and an outlet between which is formed anairflow path and in which at least the ejection head is disposed in theair flow path downstream of the inlet and upstream from the outlet,wherein the housing provides for substantially unobstructed airflowbetween the ejection head and the outlet when air traverses the airflowpath from the inlet to the outlet.
 22. A method for generating an airstream comprising a compound according to claim 21, wherein the air isdrawn from inlet to outlet.
 23. A device for delivering an aerosolizedcompound, the device comprising: a system that generates particles of adesired size that comprise a compound, wherein the system is fluidlyconnected to a reservoir, wherein the system comprises an entry port andan element to generate particles of the desired size for ejection froman ejection head of the element; and a housing comprising an inlet andan outlet between which is formed an airflow path and in which at leastthe ejection head is disposed in the air flow path downstream of theinlet and upstream from the outlet, wherein the housing provides forsubstantially non-turbulent airflow between the ejection head and theoutlet when air traverses the airflow path from inlet to outlet.
 24. Adevice for delivering an aerosolized compound, according to claim 23,wherein the housing provides for substantially laminar airflow betweenthe ejection head and outlet when air traverses the airflow path frominlet to outlet.